Monoclonal antibody Prasinezumab shows promise in slowing rapid progression of Parkinson’s disease

In a recent study published in the journal Nature Medicinea large, international team of researchers conducted an exploratory analysis to assess whether the monoclonal antibody prasinezumab, previously shown to be effective in slowing the progression of motor signs in Parkinson’s disease, actually showed benefit in subgroups of Parkinson’s disease patients with faster progression of motor degeneration.

Study: Pracinezumab slows motor progression in rapidly progressive early-stage Parkinson’s disease. Image credit: Naeblys / Shutterstock

Record

A hallmark of Parkinson’s disease is the accumulation of α-synuclein, which is thought to spread between neurons and contribute to the pathogenesis of Parkinson’s disease. One of the first therapeutic options to target aggregated α-synuclein was the monoclonal antibody prasinezumab, which was investigated in phase II clinical trials among patients with early-stage Parkinson’s disease participating in the PASADENA study.

The primary endpoint of the phase II trials of the PASADENA study was the Unified Movement Disorder Society Parkinson’s Disease Rating Scale or MDS-UPDRS score. Although the monoclonal antibody was not found to be effective in all parameters of the MDS-UPDRS, compared with subjects who received placebo, those who received pracinezumab showed a slower progression of motor-related degeneration. In addition, the team also believed that the MDS-UPDRS subscales are unlikely to show changes over short observation periods such as one year.

About the study

In the current study, the team looked at the effect of pracinezumab on slowing the progression of motor degeneration in subgroups of Parkinson’s patients who had the rapidly progressive form of the disease. Since the MDS-UPDRS subscales may not show short-term treatment-related changes, observing subgroups with the rapidly progressing form of Parkinson’s disease could help improve the signal-to-noise ratio and reveal possible treatment effects with monoclonal antibodies.

The PASADENA study included three treatments — placebo, 1,500 mg of pracinezumab and 4,500 mg of pracinezumab. Patients were randomized to the three groups after stratifying by age (over or under 60 years), sex, and monoamine oxidase B inhibitor use. Patients using other symptomatic Parkinson’s disease medications, such as dopamine agonists or levodopa at baseline, were excluded. In cases where the use of these drugs was considered imperative, MDS-UPDRS scores were calculated before starting treatment.

The present study examined the impact of prasinezumab in patients receiving stable doses of monoamine oxidase B inhibitors at baseline who had other markers of faster disease progression. Analyzes of the six primary prespecified subpopulations included in phases I and II of the PASADENA study only included the results of four subpopulations.

Subpopulations were based on monoamine oxidase B inhibitor use, stage 2 or Hoehn and Yahr stage versus stage 1 Parkinson’s disease, those with and without REM sleep behavior disorder or rapid eye movement disorder, and those with a diffuse malignant phenotype versus a non-diffuse malignant phenotype .

The analysis was also stratified into six exploratory subpopulations based on age, sex, disease duration, age at diagnosis, and motor subphenotypes such as tremor-predominant versus akinetic rigidity or postural instability gait dysfunction. In addition, since previous studies reported no dose response, the two treatment groups consisting of 1,500 mg and 4,500 mg pracinezumab were pooled for the analysis.

Results

The findings showed that pracinezumab was more effective at slowing the progression of motor signs in patients with Parkinson’s disease with the rapidly progressive form of the disease. Subpopulation analyzes revealed that patients with diffuse malignant phenotypes or those using monoamine oxidase B inhibitors at baseline, which are indicators of rapid disease progression, showed slower signs of motor-related degeneration compared with patients with phenotypes that did not rapid progression of Parkinson’s disease.

The MDS-UPDRS part III score, which corresponds to motor scores assessed by clinicians, showed a slower increase or worsening of degeneration in patients treated with pracinezumab than in those treated with placebo. Parts I and II of the MDS-UPDRS score correspond to patient-reported motor and non-motor signs, respectively.

The researchers believe that since the data showed faster progression along MDS-UPDRS part III compared to parts I and II, part III or clinician-rated motor signs may precede changes in parts I and II. These findings also suggest that more extended observation periods are needed to accurately assess the potential effect of therapies such as pracinezumab.

conclusions

Overall, the results suggested that the monoclonal antibody prasinezumab could potentially be used to slow the progression of motor-related degeneration in patients with the rapidly progressive form of Parkinson’s disease. In addition, more extended observation periods are needed to observe the impact of pracinezumab treatment in patients with the slowly progressive form of the disease. Furthermore, additional randomized clinical trials need to further validate these findings.